SC2 is a 308 residue glycoprotein highly expressed in neuronal-enriched regions of the rat central nervous system (CNS). The SC2 sequence has an unglycosylated molecular mass of 36.1 kdal and contains a putative membrane-spanning domain located near the carboxy terminus (Johnston IG et al (1992) J Neurosci Res 32:159-166). All three potential N-linked glycosylation sites are on the amino-terminal side of the membrane-spanning domain. Two tyrosine residues are present on the carboxy-terminal side of the transmembrane domain. SC2 mRNA is present throughout postnatal cerebellar development. The highest levels of SC2 expression are found in neuronal cell types, including pyramidal cells of the hippocampus, all layers of the neocortex, granule, and Purkinje neurons of the cerebellum. SC2 is also expressed at low levels in many other tissues.
Glycoproteins participate in the mechanisms of neurotransmitter release. The tightly-regulated synaptic vesicle cycle at the nerve terminal consists of the formation of synaptic vesicles, the docking of vesicles to the presynaptic plasma membrane, the fusion of these membranes and consequent neurotransmitter release, endocytosis of the empty vesicles and the regeneration of fresh vesicles. A variety of glycoproteins are involved in these processes, serving as recognition and/or adhesion molecules (reviewed in Sudhof TC (1995) Nature 375:645-653; Bennet MK and RH Scheller (1994) Curr Opin Neurobiol 4:324-329).
Glycoproteins present in the synapses of the mammalian CNS play a major role in the establishment and in the adhesive stability of synaptic contacts and in neuronal functioning. Synaptic modifications induced by learning and long-term potentiation (LTP) may involve the action of cell adhesion molecules, which include a variety of neuronal glycoproteins (Nosten-Bertrand M et al (1996) Nature 379:826-829). Cell adhesion glycoprotein molecules are involved in target recognition and synaptogenesis at neuromuscular junctions, and may play a role in fine-tuning nerve terminal arborization and in modifying the development of presynaptic functions. Defects in fasciclin I (Fas I), an insect glycoprotein expressed in motor nerve axons and terminals, result in defective presynaptic function (Zhong Y and Shanley J (1995) J Neurosci 15:6679-6687).
The processes of learning and memory establishment involve the glycoprotein-mediated structural remodeling and stabilization of synapses. Training chicks in a one-trial passive avoidance task results in a cellular cascade which includes 1) phosphorylation of the presynaptic protein kinase C substrate B-50, 2) increased synthesis of pre- and postsynaptic glycoproteins, 3) subsequent increases in dendritic spine densities, synapse and synaptic vesicle numbers, and 4) prolonged increase in neuronal bursting (Rose SP (1991) Trends Neurosci 14:390-397).
Glycoprotein-associated effects are regulated by post-translational modifications, such as variations in the structure of attached carbohydrate moieties and in phosphorylation. For example, certain synaptic glycoproteins show enhanced fucosylation in day-old chicks subjected to a passive-avoidance task. Antibodies directed against these glycoproteins cause a loss of memory of this learned response (Mileusnic R et al (1995) J Neurochem 64:2598-2606). Tyrosine phosphorylation of neuronal glycoproteins paralleling synaptic formation suggests a role for these glycoproteins in synapse development and in signal transduction (Soulliere J et al (1994) J Neurosci Res 37:506-514).
Neuronal atrophy and synapse loss has been correlated with numerous neurodegenerative disorders. The severity of Parkinson disease correlates with the degree of neuronal loss in the substantia nigra. The principal pathologic feature of Huntington disease is severe degeneration of the basal ganglia, which contain a preponderance of GABA-nergic neurons. Lower and upper motor neuron degeneration is the principal pathologic feature of amyotrophic lateral sclerosis (ALS, Lou Gehrig disease) (Boss B J et al (1994) in Pathophysiology, McCance K L and Huether S E eds, Mosby-Year, St. Louis Mo., pp.527-586). Dementia-associated disorders also involve nerve cell atrophy and degeneration. Synapse loss in brain tissue correlates with the severity of dementia in Alzheimer's disease (Lassmann H et al (1993) Ann NY Acad Sci 695:59-64). viral pathogens attach to host cell surfaces by the interaction of viral envelope glycoproteins with host membrane glycoproteins. This viral attachment is the first step in the infective cycle for numerous pathogens, including those which attack the nervous system such as poliovirus, rabies, herpes simplex, and HIV. Host cell surface glycoproteins thus provide targets for the design of anti-viral therapeutics.
Glycoproteins participate in formation and maintenance of neurons and synapses and in synaptic vesicle cycling. They are implicated in the acquisition of memory and learning. Understanding the structure and function of neuronal glycoproteins will provide insight into normal neuronal and synaptic function and their physiological and pathological modifications. The selective modulation of glycoprotein expression may provide a means for the regulation and maintenance of neurons, synapses and synaptic vesicles in neurodegenerative disorders, as well as in the control of host cell invasion by viral pathogens.